Acute renal failure (ARF) remains a major source of morbidity and mortality in hospitalized patients, complicating the course of 5-7% of hospital admissions and up to 30% of intensive care units admissions. Approximately 40% of ARF cases are defined as acute tubular necrosis (ATN). ATN is also the final common pathway in severe renal dysfunction in patients suffering from diseases of non-renal origin (so-called pre and post renal failure).
Interleukin-6 (IL-6) is a member of a family of cytokines, including leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), ciliary neurotrophic factor (CNTF), IL-11, and oncostatin M (OSM), which acts via receptor complexes that contain at least one subunit of the ubiquitously expressed signal transducing protein, gp130.
On target cells, IL-6 acts by binding to a specific cognate receptor designated interleukin-6 receptor (IL-6R), which triggers gp130 and leads to the activation of the Janus kinase (Jak)/signal transduction and activator of transcription (STAT) signaling pathway, and in particular the activation of STAT-3. Unlike the ubiquitously expressed gp130, the cellular distribution of IL-6R is limited to a few cell types including hepatocytes, and some leukocyte sub-populations including monocytes, neutrophils, and some T cells and B cells. However, the IL-6R also exists in a soluble form (sIL-6R), which together with IL-6 generates a complex that stimulates cells via direct interaction with gp130. Importantly, in a process called IL-6 trans-signaling, IL-6/sIL-6R complexes act as an agonist on cell types that, although they express gp130, would not inherently respond to IL-6 alone.
A recombinant fusion protein called Hyper-IL-6 consisting of human IL-6 linked by a flexible peptide chain to sIL-6R was shown to be a super agonistic designer cytokine (Fischer, M., et al. Nat. Biotechnol. 15: 142-145, 1997). Hyper-IL-6 was found to be more active than the combination of unlinked IL-6 and sIL-6R on gp130-expressing cells, and to exhibit a super agonistic effect both in vitro and in vivo (Peters, M., et al. J. Immunol. 161: 3575-3581, 1998).
U.S. Pat. No. 5,919,763 to Galun et al. discloses methods for treating an injury to a liver of a subject comprising administering to the subject a pharmaceutical composition comprising an IL-6/sIL-6R complex, preferably Hyper-IL-6.
International Application Publication No. WO 99/62534 of Galun et al. discloses methods for treating an injury to a liver of a subject comprising administering to the subject a pharmaceutical composition comprising an IL-6/sIL-6R complex, preferably Hyper-IL-6. WO 99/62534 further discloses methods of gene therapy for treating an injury to a liver of a subject comprising administering to the subject a vector carrying Hyper-IL-6 chimera gene.
International Application Publication No. WO 03/029281 of Axelrod et al. discloses a therapeutic composition comprising an IL-6 family combination component and a liver regenerating factor, preferably the IL-6 family combination component is a IL-6/sIL-6 complex. WO 03/029281 further discloses methods for treating a pathological condition in a subject comprising administering to the subject a therapeutic composition comprising an IL-6 family combination component and a liver regenerating factor, wherein at least one of the IL-6 family combination component and the liver regenerating factor is administered encoded by a plasmid. Among the pathological conditions listed, kidney disease including renal failure is indicated.
Leukemia Inhibitory Factor (LIF) and LIF receptor mRNA expression was shown to be increased significantly during the recovery phase after acute renal failure (Yoshino, J., et al., J. Am. Soc. Nephrol. 14: 3090-3101, 2003). The increased expression of LIF mRNA and protein was pronounced mostly in the S3 segment of the proximal tubules. It was suggested that LIF is involved in tubular regeneration after experimental acute renal failure (Yoshino, T., et al. ibid). However, no specific enablement or guidance is provided for inducing renal regeneration by LIF only or LIF-soluble LIF receptor complex after ARF.
International Application Publication No. WO 2005/113591 discloses a fusion polypeptide consisting of soluble IL-11 receptor (sIL-11R) and IL-11 and uses thereof for the treatment of a proliferative disease, a cytopathy, radiation damage, an IL-11 dependent inflammatory disorder, IL-11 dependent degenerative disorders, and IL-11 dependent or mediated soft tissue disorders.
IL-6 was shown to stimulate tubular regeneration in rats with glycerol-induced ARF (Homsi, E., et al., Nephron 92: 192-199, 2002). IL-6 administered to these rats caused a significant increase in tubular cell proliferation in the cortex and medulla, however it failed to accelerate recovery of renal function in the rats (Homsi, E., et al., ibid).
It would be highly advantageous to have improved methods for the treatment or prevention of renal failure which maintain or restore renal function and thereby reduce mortality caused by renal failure.